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Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: The Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) Trial

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Author Block: John R Teerlink, San Francisco VAMC UCSF, San Francisco, CA; Rafael Diaz, Rosario Inst of Cardiology, ROSARIO, Argentina; G. Michael Felker, Duke Clinical Res Inst, Durham, NC; Marco Metra, Univ of Brescia, Brescia, Italy; John J McMurray, BHF Cardiovascular Res Ctr, Glasgow, United Kingdom; Scott D Solomon, Brigham and Women's Hosp, Boston, MA; Lucie A Sharpsten, Amgen Inc., Thousand Oaks, CA; Jason C Legg, Amgen, Newbury Park, CA; Siddique A Abbasi, Amgen Inc., Thousand Oaks, CA; Fady I Malik, Cytokinetics Inc., South San Francisco, CA; Christopher E Kurtz, Amgen Inc., Thousand Oaks, CA; GALACTIC-HF Committees, Investigators and Patients
Disclosure Block: J.R.Teerlink: Honoraria; Modest; AstraZeneca, Research Grant; Modest; Bristol-Myers Squibb, Cytokinetics, Medtronic, Research Grant; Significant; Abbott, Amgen, Boehringer-Ingelheim, Bayer. F.I.Malik: Employment; Significant; Cytokinetics, Inc., Stock Shareholder; Significant; Cytokinetics, Inc.. C.E.Kurtz: Employment; Significant; Amgen, Inc., Stock Shareholder; Significant; Amgen, Inc.. Galactic-hf committees, investigators and patients: n/a. R.Diaz: Research Grant; Significant; DALCOR, MHICC, PHRI, AMGEN, AMARIN, Speaker/Speaker's Bureau; Modest; SANOFI. G.Felker: Honoraria; Modest; Roche Diagnostics, Novartis, Amgen, BMS, Medtronic, Cytokinetics, Research Grant; Modest; Amgen, Bayer, Merck, Research Grant; Significant; Roche Diagnostics. M.Metra: Honoraria; Modest; Amgen, Abbott Vascular, Vifor pharma, WindTree Therapeutics, Astra-Zeneca, Actelion, LivaNova, Speaker/Speaker's Bureau; Modest; Abbott Vascular, Edwards therapeutics. J.J.Mcmurray: Other; Modest; Bayer, Cardiorentis, Amgen, Oxford University/Bayer, Theracos, Abbvie, Dalcor, Pfizer, Merck, Bristol Myers Squibb (BMS), Vifor-Fresenius, Kidney Research UK (KRUK), Other; Significant; Novartis, Glaxo Smith Kline (GSK), Novartis, AstraZeneca. S.D.Solomon: Other; Modest; Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, C, Research Grant; Significant; Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Neurotronik, NIH/NHLBI, Novartis, Respicardia, Sanofi Pa. L.A.Sharpsten: Employment; Significant; Amgen, Stock Shareholder; Significant; Amgen. J.C.Legg: Employment; Significant; Amgen, Stock Shareholder; Significant; Amgen. S.A.Abbasi: Employment; Significant; Amgen.
Introduction: Impaired systolic function is the central defect in patients with heart failure with reduced ejection fraction (HFrEF). Omecamtiv mecarbil (OM) enhances myocardial contractility by potentiating the interaction between myosin and actin and, in Phase 2 studies, improved measures of cardiac systolic performance, left ventricular size, and NT-proBNP. Hypothesis: GALACTIC-HF tests the hypotheses that OM can safely reduce the risk of cardiovascular (CV) death, prevent clinical HF events, and improve symptoms in patients with HFrEF. Methods: In this Phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial, patients with chronic HF, NYHA class II-IV, LVEF ≤35%, BNP ≥ 125 pg/mL or NT-proBNP ≥ 400 pg/mL (BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL, if atrial fibrillation/ flutter) and either current hospitalization for HF or history of hospitalization or emergency department visit for HF within a year of screening were randomized to either oral placebo or OM (pharmacokinetic-guided dosing: 25, 37.5 or 50 mg bid). Key exclusion criteria included systolic blood pressure (SBP) <85 mmHg, heart rate <50 bpm, and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2 or dialysis. The primary efficacy outcome is time to CV death or first HF event (hospitalization or an urgent visit resulting in intravenous therapy for heart failure). The trial is event-driven and statistically powered for the endpoint of CV death (target ~1,590 CV deaths). Results: 8,256 patients were randomized. The 8,232 patients of the analysis set were predominantly male (79%) and white (78%) with mean age 65 years, mean SBP 116 mmHg, and median eGFR 60 mL/min/1.73 m2; 2084 (25%) were inpatients. Co-morbidities were prevalent (61% coronary artery disease, 70% hypertension, 55% hypercholesterolemia, 40% Type 2 diabetes mellitus). Patients had mean LVEF 27% with ischemic etiology in 54%, mild-to-moderate symptoms (NYHA II/III, 53%/ 44%; mean KCCQ total symptom score, 66) and median NT-proBNP 1972 pg/mL. At baseline, 87% of patients received a renin-angiotensin system blocker (1595 patients with ARNi), 94% a beta blocker, and 77% an MRA, with 65% receiving all three drug classes; 14% had a CRT and 32% had an ICD implanted. The primary results will be available for presentation at the AHA2020 meeting. Conclusions: GALACTIC-HF is the first trial to test the hypothesis that selectively improving cardiac function with a novel cardiac myosin activator, omecamtiv mecarbil, can improve outcomes in patients with HFrEF. GALACTIC-HF has enrolled a wide range of patients with excellent background therapy from both the inpatient and outpatient settings, and will provide definitive evidence of the efficacy and safety of this novel therapy, as well as informing its potential future implementation. (Funded by Amgen; EU Clinical Trials Register 2016-002299-28; clinicaltrials.gov NCT02929329)